香港中文大学Xiao-qiang Yao团队发现，内皮细胞Orai1对正常血压和高血压小鼠颈动脉的内皮依赖性收缩至关重要。2024年1月26日，《中国药理学报》杂志在线发表了这项成果。

研究人员报道了内皮细胞Ca2+进入通道Orai1在内皮依赖性收缩（EDC）中的功能作用。通过在饮用水中摄入L-NNA（0.5g/L）4周或通过渗透泵输送Ang II（1.5mg kg-1d-1）2周，在WT小鼠中建立了高血压模型。在TRPC5 KO小鼠中，L-NNA和Ang II的浓度分别增至1g/L或2mg kg-1d-1。从颈动脉和主动脉制备动脉切片，在Nω-硝基-L-精氨酸甲酯存在下用乙酰胆碱诱发EDC。

研究人员发现，低浓度乙酰胆碱（3-30nM）可使正常血压和高血压小鼠的苯肾上腺素预收缩颈动脉松弛，而高浓度乙酰胆碱（0.1-2μM）可诱导收缩。应用选择性Orai1抑制剂AnCoA4（100μM）或YM58483（400nM）对ACh诱导的松弛没有影响，但明显降低了乙酰胆碱诱导的EDC。研究人员发现，与正常血压的小鼠相比，高血压小鼠的EDC增加，这与高血压小鼠内皮细胞中Orai1的表达增加有关。与同样参与EDC的TRPC5和TRPV4相比，内皮细胞Orai1对EDC的贡献相对大于TRPC5或TRPV4本身。研究人员发现COX-2、PGF2α、PGD2和PGE2是Orai1/TRPC5/TRPV4的下游信号。

总之，Orai1与内皮细胞中的TRPC5和TRPV4共同调节EDC反应。这项研究证明了Orai1在正常血压和高血压小鼠EDC中的新功能，从而为Ca2+渗透通道控制EDC提供了一个总体方案。

据介绍，EDC存在于正常血压动物的血管中，但在高血压时会加剧。EDC的早期信号是内皮细胞中的胞质Ca2+上升。

附：英文原文

Title: Endothelial cell Orai1 is essential for endothelium-dependent contraction of mouse carotid arteries in normotensive and hypertensive mice

Author: Li, Xiao, Lei, Zhen-chuan, Lo, Chun Yin, Jan, Tsz Yau, Lau, Chi Wai, Yao, Xiao-qiang

Issue&Volume: 2024-01-26

Abstract: Endothelium-dependent contraction (EDC) exists in blood vessels of normotensive animals, but is exaggerated in hypertension. An early signal in EDC is cytosolic Ca2+ rise in endothelial cells. In this study we investigated the functional role of Orai1, a major endothelial cell Ca2+ entry channel, in EDC. Hypertension model was established in WT mice by intake of L-NNA in the drinking water (0.5g/L) for 4 weeks or osmotic pump delivery of Ang II (1.5mg·kg1·d1) for 2 weeks. In TRPC5 KO mice, the concentration of L-NNA and Ang II were increased to 1g/L or 2mg·kg1·d1, respectively. Arterial segments were prepared from carotid arteries and aortas, and EDC was elicited by acetylcholine in the presence of Nω-nitro-L-arginine methyl ester. We showed that low concentration of acetylcholine (3–30nM) initiated relaxation in phenylephrine-precontracted carotid arteries of both normotensive and hypertensive mice, while high concentration of acetylcholine (0.1–2μM) induced contraction. Application of selective Orai1 inhibitors AnCoA4 (100μM) or YM58483 (400nM) had no effect on ACh-induced relaxation but markedly reduced acetylcholine-induced EDC. We found that EDC was increased in hypertensive mice compared with that of normotensive mice, which was associated with increased Orai1 expression in endothelial cells of hypertensive mice. Compared to TRPC5 and TRPV4, which were also involved in EDC, endothelial cell Orai1 had relatively greater contribution to EDC than either TRPC5 or TRPV4 alone. We identified COX-2, followed by PGF2α, PGD2 and PGE2 as the downstream signals of Orai1/TRPC5/TRPV4. In conclusion, Orai1 coordinates together with TRPC5 and TRPV4 in endothelial cells to regulate EDC responses. This study demonstrates a novel function of Orai1 in EDC in both normotensive and hypertensive mice, thus providing a general scheme about the control of EDC by Ca2+-permeable channels.

DOI: 10.1038/s41401-024-01227-6

Source: https://www.nature.com/articles/s41401-024-01227-6

期刊信息

Acta Pharmacologica Sinica：《中国药理学报》，创刊于1980年。隶属于施普林格·自然出版集团，最新IF：8.2

官方网址：http://www.chinaphar.com

投稿链接：https://mc.manuscriptcentral.com/aphs